This transcript has been edited for clarity. 

Hello, I’m Eugene de Juan Jr, MD. I’m a professor in the department of ophthalmology at the University of California, San Francisco.

I’m giving the Henry and Frederick Sutro Memorial Lecture at Glaucoma 360. It’s a great honor to give this lecture. Over the past 12 or 13 years, this lecture has really been the high point of Glaucoma 360, with tremendous leaders in ophthalmology delivering it. It’s a great honor for me to be part of that tradition, even though I’m a little embarrassed to be speaking in the presence of such great leaders in ophthalmology and glaucoma.

The title of my talk is “Neuroprotection: The Need, the Opportunity, and the Path.”  Despite more than 100 years of lowering intraocular pressure, and the obvious benefits of doing so, too many patients still go blind, and many more experience significant impacts on quality of life. With visual field loss, patients fall more often, have more driving accidents, and experience cognitive issues. Quality of life is profoundly affected, and we need something extra to prevent this from progressing.

From an opportunity standpoint, while the need is clear, the opportunity has changed dramatically over the past 10 years. What has changed is our understanding of the pathophysiology of glaucoma, particularly axonal damage and ganglion cell soma damage. We now recognize that there are multiple drugs and drug candidates capable of protecting these cells.

Pressure at the lamina cribrosa is thought to be a key—maybe the key—cause of neural damage in glaucoma. That pressure either directly affects the ganglion cell axon or its supporting structures. The ganglion cells die, the axons go away.

There are three areas I want to focus on that are particularly exciting. One is keeping the ganglion cells alive. I’m going to focus on work involving a company I’ve been part of [Perceive Pharma] that targets the DLK/LZK pathway. The second area is axonal degeneration—specifically, Wallerian degeneration that is distal to the lamina cribrosa. The third is metabolic insults that could be modified to protect the axons as well.

A tremendous amount of work began at Johns Hopkins with Derek Welsbie, MD, PhD, and Donald L. Zack, PhD, examining the DLK/LZK pathway. Long story short, inhibition of this pathway has resulted in almost complete protection of ganglion cells in the presence of very high intraocular pressures (50 to 60 mmHg) in nonhuman primates for 30 days. This type of response is dramatic. When we first saw it, Dr. Welsbie said he got goosebumps.

Distal to the lamina cribrosa, axonal degeneration—Wallerian degeneration—is driven by low levels of NAD⁺, which is critical for axonal health. When NAD⁺ levels go down, this becomes an initiating factor in loss of the axons.

There are several strategies have been used to prevent this decrease in NAD⁺. One involves SARM1, an NAD⁺ hydrolase that depletes NAD⁺. This was developed by researchers at Washington University and seems very useful in preventing axonal degeneration by preserving NAD⁺ levels.

There are regulators of SARM1; one is called NMNAT2. When NMNAT2 expression is high, it prevents activation of the SARM1 hydrolase and, in turn, prevents depletion of NAD⁺. Finally, there is nicotinamide, a vitamin that has been shown in animals to prevent NAD⁺ depletion. Hopefully, these studies will also show benefit in human patients as well.

The final area I want to highlight is vascular support of the optic nerve. A company called Perfuse Therapeutics is targeting the endothelium. Endothelin is a potent vasoconstrictor, and antagonizing it may prevent vasoconstriction. This drug has been shown to improve visual field function, improve blood flow, and possibly improve structure.

All these opportunities will need to be tested in the clinic, and clinical trial design is critical. Historically, glaucoma trials have required thousands of patients followed for up to 4 years, with a very high bar set by the US Food and Drug Administration (FDA). The FDA guidance from more than 15 years ago relied on 5 prespecified visual field points with a 7-dB loss in sensitivity. Since that time, we have found that trend-based analyses, including mean deviation, differ from event-based progression. What is now commonly referred to as “FDA7” is a more powerful way to doing clinical tests. Selecting fast progressors can amplify the signal earlier. AI-based enrichment strategies can help identify patients likely to progress, and cluster testing—concentrating tests early and at the endpoint—can further strengthen the signal.

By combining these approaches appropriately, we may be able to reduce clinical trials from thousands of patients to hundreds. To me, this is extremely exciting. It’s an area strongly supported by the Glaucoma Research Foundation, and I believe the FDA will respond.

That’s what I want to leave you with today: how important this work is, and how exciting the future is as well. Thank you. GP