An anti-amyloid drug for blindness

An Amsler grid has a simple design: It’s just a piece of white paper with black gridlines and a dot in the middle. But ophthalmologists use it to track complex changes in their patients’ eyes. When someone looks at the central dot and notices newly wavy gridlines or fresh blank spots, those are worrying signs of worsening vision loss due to a retinal disease like age-related macular degeneration (AMD).

Much like Alzheimer’s disease and other neurodegenerative conditions, AMD’s specific combination of causes varies from person to person. “The most severe risk factor is age,” Omer Trivizki, an ophthalmologist at Tel Aviv University who serves on the scientific advisory board of Galimedix Therapeutics, a neuropharmaceutical company. In 2019, researchers estimated that just under 12 percent of Americans over the age of 40 showed the first signs of the disease (1).

Over the course of several years, AMD progresses from an asymptomatic early stage, in which ophthalmologists first detect yellow, waste-filled deposits called drusen under a person’s retina, to a late stage, which culminates in irreversible loss of vision. Whether a person will develop AMD later in life depends on their genetics, lifestyle, and medical history (2). These and other factors can also affect the rate at which AMD progresses after the first drusen appear (3).

Drusen do not cause blindness, but their contents contain clues that could point to the real culprits. Among the other fats and proteins, researchers have identified beta-amyloid, the same protein that turns toxic and forms plaques in the brains of people with Alzheimer’s disease (4). In fact, multiple research groups have drawn connections between the pathologies of the two progressive disorders (5,6).

Hermann Russ, a neurologist who co-founded Galimedix Therapeutics and who now serves as the company’s Chief Scientific Officer, thinks targeting the molecule offers a promising approach to treating AMD. In December 2024, his company launched a Phase 2 clinical trial to the test the safety and efficacy of their new eyedrop, GAL-101. Russ is confident that their drug’s unique mechanism of disrupting toxic beta-amyloid activity will translate into clinical success, and he and his colleagues envision treating AMD as the first of several uses for the molecule they’ve developed.

From inhibiting VEGF and complement to something new

For over 20 years, ophthalmologists have recommended vitamin and nutrient supplements to slow down the progression of intermediate AMD (7,8). At this stage, some people notice abnormalities in their vision, such as mild blurriness or difficulties seeing at night. But severe loss of vision does not occur until a person approaches the disease’s endpoint.

Hermann Russ in a gray collared shirt. — Galimedix Chief Scientific Officer Hermann Russ wants to use the small molecule GAL-101 to disrupt the toxic effects of beta-amyloid and treat retinal diseases and neurodegenerative disorders.
Credit: Galimedix Therapeutics, Inc

Not all cases of late-stage AMD are the same. Historically, most people who have become legally blind because of AMD have developed the “wet” variety (9). In wet AMD cases, excessive growth of new blood vessels results in bleeding under the retina and other complications that can cause rapid deterioration in a person’s vision. However, since 2004, eye injections designed to block vascular endothelial growth factor (VEGF) — a protein that promotes the growth of new blood vessels — have reduced rates of blindness linked to wet AMD (10).

These drugs are not perfect because some people have or develop resistance to them, and researchers continue to push for improvements (11). Still, the injections offer an effective treatment strategy when people have reached late-stage wet AMD. “We have the anti-VEGF drugs, which keep improving from time to time,” said Trivizki. “Dry AMD is not the same.”

AMD starts out dry — in other words, without excessive growth of new blood vessels — for every person, and for many it can remain dry throughout the course of the disease. But people who never develop wet AMD can still become blind. In late-stage dry AMD, a person loses vision when patches of the cells at the center of their retinas die, a condition called geographic atrophy (GA).

Identifying effective drug targets for late-stage dry AMD has proved challenging. Early efforts to stop this process have focused on inhibiting the complement cascade, a group of proteins that promote inflammation (12). Although in 2023 the FDA approved two drugs that target proteins in this cascade based on evidence that they limit the growth of GA lesions, neither treatment had an effect on people’s actual ability to see (13).

Trivizki said that there was a general sense of disappointment among ophthalmologists regarding complement inhibitors. “We expected more,” he said. “The race is still ongoing.”

We have the anti-VEGF drugs, which keep improving from time to time. … Dry AMD is not the same.
– Omer Trivizki, Tel Aviv University

That’s why he was excited to work with Galimedix Therapeutics when the company reached out to him to help design their clinical trial for GAL-101. While the complement cascade plays a role in AMD disease progression by killing damaged neurons in the retina, ophthalmologists have grown increasingly interested in protecting these cells from the initial damage that precipitates the immune response (14). And Trivizki thinks the evidence that beta-amyloid proteins have toxic effects on neurons and their presence in drusen make them a strong potential therapeutic target (15).

“Maybe you can actually stop this neurotoxin,” he said. “And maybe you can improve your patient’s life and not only stop disease progression.”

A new strategy for disrupting toxic beta-amyloid

Galimedix Therapeutics is not the first company to try treating AMD by targeting beta-amyloid. In 2018, GlaxoSmithKline reported that GSK933776, a monoclonal antibody designed to bind to beta-amyloid, had no effect on the growth of GA lesions in people who received intravenous infusions of the drug (16). But Russ thinks that previous effort failed for the same reason that many anti-amyloid antibodies have failed in clinical trials for Alzheimer’s disease (17).

“They are nonspecific,” he said.

The neurons of people with Alzheimer’s disease, AMD, and other neurological diseases contain abnormal deposits of misfolded beta-amyloid, but the protein is present in everyone’s brain. It appears to play important roles in the normal functions of the central nervous system (18). At the same time, Russ said that researchers have placed too much emphasis on the beta-amyloid that neurons have already sequestered into abnormal plaques or drusen.

“This is not the problem; the problem is several steps before,” he said.

Before misfolded copies of beta-amyloid clump up and lose their ability to move freely, they form smaller, free-floating oligomers, which appear to cause the toxic effects associated with the protein (19). Anti-amyloid antibodies that have demonstrated some level of clinical success have targeted these soluble aggregations of the protein (20).

Whereas antibody treatments tend to target plaques, which are already inert, or oligomers, which can start doing damage as soon as they form, the small molecule GAL-101 binds to individual beta-amyloid proteins before they aggregate into toxic oligomers (21-23). More specifically, the drug targets a stretch of amino acids that becomes accessible in misfolded copies of beta-amyloid 42, the form of the protein that ultimately makes up the bulk of the insoluble aggregations. “Preventing the formation should be the pharmacologically more efficient way,” said Russ.

Putting it to the test and going from there

Since GAL-101 was first described in 2009, Russ and his colleagues have collected evidence that the drug protects against neuronal damage in animal models of Alzheimer’s disease and retinal diseases (24-27). Now, for the first time, Galimedix Therapeutics’ Phase 2 clinical trial will test GAL-101’s efficacy in people. The study will include adults over the age of 55 who have GA lesions resulting from AMD, and the participants will self-administer two drops of the drug every day for at least a year. Throughout that time, clinicians will monitor the size of the participant’s GA lesions and look for changes around the periphery of their retinas as well.

“The idea is to show the patient actually improves,” said Trivizki. “Whatever is dead is dead. But what’s happening around the lesion?”

A diagram of the human retina above images of a normal retina and retinas affected by wet and dry macular degeneration. — Age-related macular degeneration causes gradual loss of vision as the cells of the retina die.
Credit: iStock/ttsz

Trivizki also pushed for Galimedix Therapeutics to enroll participants with relatively small GA lesions, and if the trial proves successful, he would like to see efforts to administer the drug even earlier. “We need to catch the disease once it’s only drusen and stop it over there, so we won’t get to the GA lesions,” he said.

Russ agreed that earlier interventions will always produce better outcomes for people with AMD, but he thinks GAL-101’s ability to prevent the formation of beta-amyloid oligomers could make the drug beneficial for people at all stages of the disease. “Even patients who have not anymore the dry form of AMD — they have already the late-stage wet form — they should also have advantages,” he said, “because the neurodegenerative process continues and continues.”

Russ and Galimedix Therapeutics have plans to use GAL-101 for other neurodegenerative conditions as well. In addition to one day attempting to treat Alzheimer’s disease with an orally administrated version of their drug, Russ sees the GAL-101 eyedrop as a potential therapeutic for another leading cause of blindness in the elderly: glaucoma (28).

While researchers are increasingly considering neuroprotection to stop the degeneration of the optic nerve in people with glaucoma, the connection between beta-amyloid and that disease is not as well established as the connection between the neurotoxin and AMD (29). But it’s another complicated disease without a cure, and current treatment options leave room for improvement (30).

Ophthalmologists like David Fleischman at the University of North Carolina at Chapel Hill won’t be entirely convinced that GAL-101 is the right medication for AMD or glaucoma until Galimedix Therapeutics produces strong clinical evidence. Still, Fleischman appreciates the risk that Russ and his company are taking. “I’m glad that there’s folks that are working and thinking outside of the box,” he said.

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