Disease-modifying glaucoma drugs

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Introduction Glaucoma is a chronic eye disease where nerve cells in the retina and optic nerve gradually die, often causing blindness if untreated. For decades, the main proven treatment has been lowering intraocular pressure (IOP) – the fluid pressure inside the eye – to slow damage (). This is done with eye drops, laser or surgery. But pressure isn’t the whole story. Many patients still lose vision even when their pressure is well-controlled. In fact, about one-third of treated patients eventually go blind in one eye (). And some people (so-called “normal-tension” glaucoma) get damage even with normal pressure. These facts tell us that simply draining fluid is not enough. Glaucoma is fundamentally a neurodegenerative disease – nerves are dying. Scientists are now exploring whether new drugs can modify the disease itself rather than just treating pressure, by protecting the nerves and improving the eye’s blood supply. In this article, we’ll explain what “disease-modifying” means in glaucoma and why it’s exciting. We’ll look at the importance of ocular blood flow and the endothelin pathway (which can choke blood vessels), and how improving blood flow or cell health might save vision. We’ll also cover PER-001, a new drug in development by Perfuse Therapeutics (now owned by Bayer), which targets endothelin. We’ll weigh the evidence – what’s been shown so far in small trials, what’s still uncertain – and discuss what the future might hold in 3–10 years. The tone is hopeful but realistic: disease-modifying therapies could change how we treat glaucoma, but they are not cures (at least not yet). What “Disease-Modifying” Means in Glaucoma A disease-modifying therapy is one that changes the course of the disease itself, instead of just relieving symptoms. In glaucoma, that would mean a drug that actually slows or stops the nerve-cell death in the eye, not just reduces pressure. It’s a bit like how some arthritis drugs do more than just mask pain by slowing joint damage. For glaucoma, the idea is often called “neuroprotection” – protecting the retinal ganglion cells (RGCs), the neurons that carry vision signals from the eye to the brain. A classic definition says neuroprotection is treating glaucoma “by a mechanism independent of lowering IOP” (). Right now, no therapy has been proven to do this in patients. In large, decades-long studies only pressure lowering showed a clear benefit. In fact, a 2023 review in Molecular Aspects of Medicine notes that “current strategies only target intraocular pressure… and do not directly target the neurodegenerative processes” of glaucoma (). It adds that up to 40% of patients still progress to blindness in at least one eye despite strict pressure control (). So researchers say we urgently need therapies that go beyond pressure. In plain terms: imagine the optic nerve as a plant that not only needs the right water pressure but also good soil and light. Pressure drops help water travel (good!), but if the root cells are sick or starved, the plant will still die. Disease-modifying treatments aim to brighten the light or improve the soil – directly helping the cells survive and function. Blood Flow and Endothelin: Why They Matter One big area of research is improving ocular blood flow. The retina is one of the body’s hungriest tissues for oxygen and nutrients. It’s like a high-performance engine needing constant fuel. If blood flow to the retina or optic nerve is compromised, cells can suffer from ischemia (lack of oxygen). Over time, even shortfalls in blood supply can kill retinal ganglion cells. Many people with glaucoma have vascular issues: for example, some have a condition called Flammer syndrome (blood vessels that over-react) or low blood pressure at night, which can worsen eye blood flow. In normal-tension glaucoma (glaucoma at normal pressures), poor blood flow is thought to be a key culprit. Scientific studies support this. For example, an experiment showed that giving endothelin-1 (a natural chemical) to animals reduced blood flow in the retina and optic nerve, causing ischemic damage (). The same molecule, endothelin-1, also raises pressure and promotes optic nerve injury (). Endothelin is perhaps the most potent vasoconstrictor in the human body () – imagine it like a very strong clamping of blood vessels. In glaucoma patients, blood levels of endothelin-1 tend to be higher than normal. Researchers even found that blocking endothelin receptors in healthy animals had no effect on normal flow, but giving extra endothelin caused a big drop in blood flow (). In other words, endothelin ramps up only when things are already bad. Why is this important? If endothelin-1 is high in glaucoma, it could constrict the small vessels in the eye, depriving nerve cells of oxygen. A 2011 review on endothelin in glaucoma put it neatly: increased endothelin can “lead to pathological changes in the retina and optic nerve head which is assumed to contribute to the degeneration of retinal ganglion cells” (). In simpler terms, high endothelin is like turning down the road supply to the optic nerve while also turning up the pressure, double-whammying the nerve. Therefore, drugs that block endothelin (called endothelin receptor antagonists) could in theory keep vessels open and protect nerves. Is there evidence OBF (ocular blood flow) matters in patients? Measurements of blood flow in glaucoma eyes often show abnormalities, and the risk of glaucoma goes up if perfusion pressure (blood pressure minus IOP) is too low (). Clinically, some glaucoma patients benefit from treatments that improve ocular perfusion (for example, some doctors manage blood pressure or use calcium channel blockers off-label). But so far, there is no approved glaucoma drug whose main action is boosting blood flow. That’s changing in research: the idea is that if we can safely open up the eye’s blood vessels or correct vascular dysregulation, we might protect the optic nerve from ischemic damage. Mitochondria and Retinal Cell Survival Another cutting-edge concept is mitochondrial protection. Mitochondria are the “power plants” of cells, and retinal ganglion cells have extremely high energy demands. They need a lot of ATP to maintain their long axons and signaling in the retina. In glaucoma, several stresses (high pressure, free radicals, inflammation) can damage mitochondria, leading to energy failure and eventually cell death. Some genetic forms of optic neuropathy (like Leber’s hereditary optic neuropathy) show that mitochondrial DNA problems cause RGC death. In glaucoma, even without a genetic mutation, chronic stress may overload the mitochondria. Researchers are testing ways to keep mitochondria healthy in glaucoma. For instance, nicotinamide (vitamin B3), which boosts the mitochondrial energy molecule NAD+, has shown promise. In a small phase 2 trial, giving glaucoma patients a combination of nicotinamide and pyruvate (another metabolic fuel) led to a short-term improvement in visual function for many participants (). The treated patients had more visual field test points that got better (not just stopped worsening) over a couple of months compared to placebo (). Although this was a very short-term result and not yet evidence that visual loss is permanently slowed, it suggests that helping RGCs with extra fuel can improve how well they work. There are other mitochondrial and cell-targeting strategies under study. Some are antioxidants (to mop up free radicals) and others are drugs that block programs of cell death. For example, experimental treatments that pre-condition cells (using mild stress like low oxygen) can activate built-in survival genes () – this “stress response” can make RGCs temporarily more resilient. Another approach is using neurotrophic factors (like brain-derived neurotrophic factor or BDNF) or growth factors to encourage cell survival. In fact, an eye drop containing nerve growth factor (rhNGF) is now in early trials for glaucoma (), aiming to block the signal that tells RGCs to die. However, it’s important to note that most of these strategies are experimental. For instance, memantine (an Alzheimer’s drug thought to protect nerve cells by blocking glutamate toxicity) underwent large clinical trials but did not significantly slow glaucoma compared to placebo (). So, while metabolic and protective approaches are very promising in concept, proof of lasting benefit in patients is still pending. PER-001 and Other Disease-Modifying Approaches A big hope in the field right now is a drug called PER-001 (from Perfuse Therapeutics, soon to be Bayer) – an intravitreal (inside-the-eye) implant of an endothelin receptor antagonist. This is exactly the strategy of blocking endothelin discussed above. PER-001 slowly releases a small molecule that blocks endothelin receptors in the eye every six months or so (). The idea is to keep eye blood vessels open, reduce inflammation, and protect retinal cells, in addition to helping lower pressure through better outflow. What do we know about PER-001 so far? Perfuse and Bayer have released encouraging early results. In a phase 1/2a study presented in 2025, a single PER-001 injection improved visual function and retinal structure compared to control over

Transcript

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Introduction. Glaucoma is a chronic eye disease where nerve cells in the retina and optic nerve gradually die, often causing blindness if untreated. For decades, the main proven treatment has been lowering intraocular pressure, IOP, the fluid pressure inside the eye, to slow damage. This is done with eye drops, laser, or surgery. But pressure isn't the whole story. Many patients still lose vision even when their pressure is well controlled. In fact, about one-third of treated patients eventually go blind in one eye, and some people, so-called normal tension glaucoma, get damage even with normal pressure. These facts tell us that simply draining fluid is not enough. Glaucoma is fundamentally a neurodegenerative disease. Nerves are dying. Scientists are now exploring whether new drugs can modify the disease itself rather than just treating pressure, by protecting the nerves and improving the eye's blood supply. In this article, we'll explain what disease modifying means in glaucoma and why it's exciting. We'll look at the importance of ocular blood flow and the endothelin pathway, which can choke blood vessels, and how improving blood flow or cell health might save vision. We'll also cover PR01, a new drug in development by Perfuse Therapeutics, now owned by Bayer, which targets endothelin. We'll weigh the evidence, what's been shown so far in small trials, what's still uncertain, and discuss what the future might hold in three ten years. The tone is hopeful but realistic. Disease modifying therapies could change how we treat glaucoma, but they are not cures, at least not yet. What disease modifying means in glaucoma? A disease-modifying therapy is one that changes the course of the disease itself, instead of just relieving symptoms. In glaucoma, that would mean a drug that actually slows or stops the nerve cell death in the eye, not just reduces pressure. It's a bit like how some arthritis drugs do more than just mask pain by slowing joint damage. For glaucoma, the idea is often called neuroprotection, protecting the retinal ganglion cells, RGCs, the neurons that carry vision signals from the eye to the brain. A classic definition says neuroprotection is treating glaucoma by a mechanism independent of lowering IOP. Right now, no therapy has been proven to do this in patients. In large, decades-long studies, only pressure lowering showed a clear benefit. In fact, a 2023 review in molecular aspects of medicine notes that current strategies only target intraocular pressure and do not directly target the neurodegenerative processes of glaucoma. It adds that up to 40% of patients still progress to blindness in at least one eye despite strict pressure control. So researchers say we urgently need therapies that go beyond pressure. In plain terms, imagine the optic nerve as a plant that not only needs the right water pressure, but also good soil and light. Pressure drops help water travel, good. But if the root cells are sick or starved, the plant will still die. Disease-modifying treatments aim to brighten the light or improve the soil, directly helping the cells survive and function. Blood flow and endothelin, why they matter. One big area of research is improving ocular blood flow. The retina is one of the body's hungriest tissues for oxygen and nutrients. It's like a high-performance engine needing constant fuel. If blood flow to the retina or optic nerve is compromised, cells can suffer from ischemia, lack of oxygen. Over time, even shortfalls in blood supply can kill retinal ganglion cells. Many people with glaucoma have vascular issues. For example, some have a condition called flammer syndrome, blood vessels that overreact, or low blood pressure at night, which can worsen eye blood flow. In normal tension glaucoma, glaucoma at normal pressures, poor blood flow is thought to be a key culprit. Scientific studies support this. For example, an experiment showed that giving endothelin-1, a natural chemical, to animals reduced blood flow in the retina and optic nerve, causing ischemic damage. The same molecule, endothelin-1, also raises pressure and promotes optic nerve injury. Endothelin is perhaps the most potent vasoconstrictor in the human body. Imagine it like a very strong clamping of blood vessels. In glaucoma patients, blood levels of endothelin-1 tend to be higher than normal. Researchers even found that blocking endothelin receptors in healthy animals had no effect on normal flow, but giving extra endothelin caused a big drop in blood flow. In other words, endothelin ramps up only when things are already bad. Why is this important? If endothelin-1 is high in glaucoma, it could constrict the small vessels in the eye, depriving nerve cells of oxygen. A 2011 review on endothelin in glaucoma put it neatly. Increased endothelin can lead to pathological changes in the retina and optic nerve head, which is assumed to contribute to the degeneration of retinal ganglion cells. In simpler terms, high endothelin is like turning down the road supply to the optic nerve while also turning up the pressure, double whammying the nerve. Therefore, drugs that block endothelin, called endothelin receptor antagonists, could in theory keep vessels open and protect nerves. Is there evidence OBF ocular blood flow matters in patients? Measurements of blood flow in glaucoma eyes often show abnormalities, and the risk of glaucoma goes up if perfusion pressure, blood pressure minus IOP, is too low. Clinically, some glaucoma patients benefit from treatments that improve ocular perfusion. For example, some doctors manage blood pressure or use calcium channel blockers off-label. But so far, there is no approved glaucoma drug whose main action is boosting blood flow. That's changing in research. The idea is that if we can safely open up the eye's blood vessels or correct vascular dysregulation, we might protect the optic nerve from ischemic damage. Mitochondria and retinal cell survival. Another cutting-edge concept is mitochondrial protection. Mitochondria are the power plants of cells, and retinal ganglion cells have extremely high energy demands. They need a lot of ATP to maintain their long axons and signaling in the retina. In glaucoma, several stresses, high pressure, free radicals, inflammation, can damage mitochondria, leading to energy failure and eventually cell death. Some genetic forms of optic neuropathy, like Lieber's hereditary optic neuropathy, show that mitochondrial DNA problems cause RGC death. In glaucoma, even without a genetic mutation, chronic stress may overload the mitochondria. Researchers are testing ways to keep mitochondria healthy in glaucoma. For instance, nicotinamide, vitamin B3, which boosts the mitochondrial energy molecule NAD plus, has shown promise. In a small phase 2 trial, giving glaucoma patients a combination of nicotinamide and pyruvate, another metabolic fuel, led to a short-term improvement in visual function for many participants. The treated patients had more visual field test points that got better, not just stopped worsening over a couple of months compared to placebo. Although this was a very short-term result, and not yet evidence that visual loss is permanently slowed, it suggests that helping RGCs with extra fuel can improve how well they work. There are other mitochondrial and cell targeting strategies under study. Some are antioxidants to mop up free radicals, and others are drugs that block programs of cell death. For example, experimental treatments that precondition cells using mild stress like low oxygen can activate built-in survival genes. This stress response can make RGCs temporarily more resilient. Another approach is using neurotrophic factors like brain-derived neurotrophic factor or BDNF, or growth factors to encourage cell survival. In fact, an eyedrop-containing nerve growth factor, RHNGF, is now in early trials for glaucoma, aiming to block the signal that tells RGCs to die. However, it's important to note that most of these strategies are experimental. For instance, memantine, an Alzheimer's drug thought to protect nerve cells by blocking glutamate toxicity, underwent large clinical trials but did not significantly slow glaucoma compared to placebo. So, while metabolic and protective approaches are very promising in concept, proof of lasting benefit in patients is still pending. PIR-001 and other disease-modifying approaches. A big hope in the field right now is a drug called PIR-001 from Perfuse Therapeutics, soon to be Bayer, an intravitrial inside-the-eye implant of an endothelin receptor antagonist. This is exactly the strategy of blocking endothelin discussed above. PER-001 slowly releases a small molecule that blocks endothelin receptors in the eye every six months or so. The idea is to keep eye blood vessels open, reduce inflammation, and protect retinal cells, in addition to helping lower pressure through better outflow. What do we know about PER01 so far? Perfuse and Bayer have released encouraging early results. In a phase one-half A study presented in 2025, a single PER-001 injection improved visual function and retinal structure compared to control over 24 weeks. In plain terms, patients who got PR01 not only saw better on tests, but their optic nerve scans, like OCT, looked healthier. Importantly, they also measured that ocular blood flow increased in treated eyes, confirming the drug was hitting its target. In a later phase 2 trial, the companies report that some glaucoma patients actually gained vision back over six months, what they call reversed progressive vision loss, while controls continued to worsen. As a reference, nearly all existing glaucoma trials simply slow vision loss, seeing any improvement is unusual. Most of these PR-001 results are reported by the company in press releases, not in a peer-reviewed journal yet. Still, they have attracted major attention. Bayer alone announced plans to acquire Perfuse in 2026, noting PR-01's potential as one of the first disease-modifying treatments for both glaucoma and diabetic retinopathy. Bayer's press release specifically highlights that PR-001 is being studied for its ability to improve the visual field for glaucoma patients and to reduce ischemia in diabetic eyes. These phrases mean the drug is not just lowering pressure, but aiming to improve nerve function and blood flow. However, caution is warranted. These results so far come from small trials, tens of patients, and company press statements. We do not yet have independent published data to review, and large studies can sometimes disappoint earlier excitement. It's also worth noting that Pair 01 is delivered as an eye injection implant, a more invasive route than simple eye drops. Patients may need to weigh the benefits against the burdens, though an injection every six months is fairly convenient compared to daily drops. Other disease-modifying ideas are still at an earlier stage. For example, eye drops or devices delivering neurotrophic factors like NGF are in early trials, and lifestyle strategies like exercise or supplements are being explored. No other specific drug for advanced neuroprotection in glaucoma has shown conclusive success in humans yet. Evidence, strong versus speculative. What evidence do we have? Strong evidence exists that lowering IOP helps most patients. This is supported by decades of clinical trials. Beyond that, evidence is still emerging. The perfuse-Bayer data on PR01 are intriguing but preliminary. Similarly, the nicotinamide trial showed short-term vision improvements. But it's not known if that will translate into long-term protection. Animal and laboratory studies give strong rationale for these approaches, e.g., it's well documented that ischemia and mitochondrial damage hurt RGCs, but animal models don't always predict human outcomes. On the weak or speculative side, many treatments that looked good in the lab have failed in people. Besides memantine, other antioxidants and supplements have had mixed results outside early studies. Gene therapies or stem cell treatments are theoretically possible, but at this point they are more futuristic and not in any advanced glaucoma trials. We also don't know the full risks of some neuroprotective agents in the eye. In short, we are optimistic but not proven. The therapies could slow glaucoma by protecting nerves, but that remains to be firmly established in clinical studies. Looking ahead, three ten years, what might realistically reach patients in the next decade? The short answer is hopefully something, but it will take time. If Per01's mid-stage trials, phase 2B3, are successful, an FDA or EMA approval could be possible by the early 2030s. That's roughly 7 to 10 years away. In the nearer term, 3 to 5 years, we'll see more results from ongoing trials. For instance, Perfuse planned a pivotal trial in late 2025, its outcomes in two, three years will be key. Other companies and academic groups are likely testing the related endothelin blockers and neuroprotective drops. Some changes don't require new FDA approvals. Doctors might start recommending vitamins or supplements like nicotinamide off-label if larger studies confirm benefits, since it's relatively low risk. There might also be new uses of existing drugs, for example, calcium channel blockers for vascular support, guided by research. Importantly, ophthalmologists and patients should stay informed. About 20 years ago, no one expected the first selective rho kinase inhibitor, nitarsudil, and nodonating prostaglandin, Letanoprostine bunod, would come along. It's possible that even treatments designed for other eye diseases, like implants for retina ischemia in diabetic patients, could be tested in glaucoma too. That said, it's realistic to say we're not about to cure glaucoma in the next few years. Even if disease-modifying drugs do arrive, they will likely be added on top of the standard IOP lowering treatments, not replacing them entirely. In the best case scenario, a patient might keep taking pressure-lowering drops and also get an injection or eye drop that helps protect their optic nerve. Over 10 years, we may see gradual improvements, some patients maintaining vision longer, fewer advancing to blindness. But we must also be prepared for setbacks. Clinical research is full of surprises, both good and bad. If a large trial fails, as happened with Mementine, that is valuable information too, guiding researchers to other targets. Conclusion. The search for disease-modifying glaucoma treatments is one of the most exciting areas in eye research today. The basic idea is clear. Pressure lowering helps many patients, but not all. Improving blood flow, blocking harmful molecules like endothelin, and directly strengthening nerve cells could in principle protect vision further. New drugs like PER001 are putting these ideas to the test. Early signs are encouraging. For example, one trial reported improved optic nerve blood flow and vision with an endothelin blocker, but we have to remember the early stage of this work. For now, the best approach remains diligent eye pressure control and regular checkups, as proven by long-term studies. Patients should discuss with their doctors about lifestyle factors like blood pressure, exercise, nutrition that support eye health. Over the next five to ten years, we may realistically see the first drug approved to slow glaucoma by protecting nerves, a milestone, though still far from a cure. Until then, it's wise to be hopeful but cautious. Each new research finding brings us a step closer, but no magic bullet has emerged yet. Science is making progress. One day, these strategies might transform glaucoma care, but it will be a process. Patients can look forward to more tools while still relying on the treatments that are proven today. Summary, lowering eye pressure remains the mainstay for glaucoma, but it doesn't halt disease for everyone. Researchers are pursuing disease-modifying therapies, aiming to directly protect retinal nerves by improving blood flow, blocking vasoconstrictors like endothilin, and boosting cellular energy. The drug PR001, an endothelin blocker implant, is a leading example. Early results suggest it can increase optic nerve blood flow and even improve vision in some patients. Other ideas, vitamins, neurotrophic factors, etc., are in smaller trials. However, all such evidence is preliminary. We need larger clinical trials to prove that these approaches truly slow glaucoma. In the next few years, watch for trials of Pier001 and similar drugs. In 10 years, we might see the first approved neuroprotective glaucoma treatment. Until then, patients should remain optimistic yet realistic. These developments are exciting, but the cure for glaucoma has not yet arrived. 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